Pharmacokinetic (PK) profile and food effect of RP-3500, a highly potent and specific inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein kinase in patients (pts) with cancer
Lheureux, S Rosen, E Lee, E Spigel, D Hojgaard, M Fontana, E. Mettu, N B Carter, Louise Patel, S Papp, R
Lheureux, S
Rosen, E
Lee, E
Spigel, D
Hojgaard, M
Fontana, E.
Mettu, N B
Carter, Louise
Patel, S
Papp, R
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Abstract
"Background: RP-3500 is an oral ATR inhibitor (ATRi) in development for the treatment of
patients (pts) with advanced solid tumors carrying alterations in ATRi-sensitizing genes.
The dose-escalation portion of the TRESR study (NCT04497116) evaluated RP-3500
5e200 mg once daily (QD) or twice daily at defined intermittent schedules in 120 pts. Methods: RP-3500 plasma levels were assessed and PK parameters were determined
by non-compartmental analysis (Phoenix WinNonLin) in pts with evaluable plasma
concentration-time points. To determine the effect of food on RP-3500 PK, 12 pts
received a single dose of RP-3500 following a standard high-fat meal on Day -3 and
after a 24-hr fast on Day 1. Serial blood samples were collected for PK analysis at
baseline and after RP-3500 administration.
Results: 120 pts had sufficient data on day 1, cycle 1, to report PK parameters.
Overall, 323 plasma concentration-time profiles were collected. Plasma exposure was
dose-linear with low within-pt variability and a T½ of w6 hr. No accumulation of
RP-3500 was observed after multiple doses were given. At therapeutic doses of 120
mg and 160 mg QD on day 1, cycle 1, mean AUC0-24 was 33.6 and 48.2 mg٠hr/mL,
respectively, and mean Cmax was 5.74 and 7.64 mg/mL, respectively. Within the
therapeutic dose range, median Tmax was 2 hr (range 0.5e6). When administered with
a high fat meal, RP-3500 median Tmax was delayed by 3 hrs and mean Cmax
was reduced by 45% compared with fasting values within this cohort. Mean AUC0-24
was 16% lower compared with AUC0-24 in the fasted state. Importantly, the plasma
levels required for the pharmacological activity of RP-3500 did not substantially differ
between the fed and fasted states.
Conclusions: The PK profile of RP-3500 is predictable with low observed variability.
RP-3500 given orally to pts at recommended doses of 120-160 mg QD on 3 days/
week, with or without food, reaches or exceeds preclinically defined target exposure
requirements (Roulston et al., Mol Cancer Ther. 2021). RP-3500 can be administered
with or without food without affecting PK parameters relevant to tolerability and
therapeutic window."
Affiliation
Description
Date
2022
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Lheureux, S, Rosen, E, Lee, E, Spigel, D, Hojgaard, M, Fontana, E, Mettu, N B, Carter, Louise, Patel, S, Papp, R, May, S, Nejad, P, Ulanet, D, Wainszelbaum, M, Manley, P, Koehler, M, Fretland, A. J, Plummer, R Yap, T A. Pharmacokinetic (PK) profile and food effect of RP-3500, a highly potent and specific inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein kinase in patients (pts) with cancer . Annals of Oncology . 2022